1. Field of the Invention
The present invention relates to O.sup.6 -benzyl-substituted guanine compounds which exhibit the ability to deplete O.sup.6 -alkylguanine-DNA alkyltransferase (AGT) activity and to methods for the administration thereof to enhance chemotherapeutic treatment of tumor cells. More specifically, the present invention relates to O.sup.6 -benzylguanine and related O.sup.6 -benzylguanine derivatives wherein the benzyl substituent may be substituted at the ortho, meta or para position. The present invention also relates to methods for administering compositions containing these compounds to a host in order to reduce the activity of AGT in tumor cells of the host which increases host responsiveness to anti-neoplastic alkylating agents such as streptozotocin, procarbazine or dacarbazine as well as to chloroethylating agents, such as chloroethylnitrosoureas or chloroethyl triazenes, subsequently or simultaneously administered to the host.
2. Description of Related Art
Chemotherapeutic chloroethylating agents have some clinical utility against a number of neoplasms but in general have only limited effectiveness in killing tumor cells. The marginal usefulness of these agents may be explained on a cellular level by the local concentration of DNA repair proteins present in the tumor. There is strong evidence that the repair protein, O.sup.6 -alkylguanine-DNA alkyltransferase (AGT), present to some degree in all mammalian tumors studied to date, is responsible for protecting cells from the antitumor effects of chloroethylating agents such as chloroethylnitrosoureas. The AGT acts to remove the initial DNA adduct formed at the O.sup.6 -position of guanine by these agents before this adduct can be converted to a lethal lesion. Efforts to reduce the level of AGT in order to increase the sensitivity of cells to the chemotherapeutic effects of chloroethylating or other alkylating agents would be advantageous to therapy which involves cytotoxic lesions at the O.sup.6 -position of guanine. Furthermore, a specific decrease in AGT levels allows one to study the biological effects of alkylating agents.
Previous studies have indicated that the chemotherapeutic effectiveness of chloroethylating and methylating agents can be enhanced in human cells in culture by pretreatment with O.sup.6 -alkylguanines. Earlier investigations demonstrated that agents such as O.sup.6 -methyl-and O.sup.6 -n-butylguanine decreased AGT levels in human tumor cells in culture which led to an enhancement in the sensitivity of these cells to the cytotoxic effects of chloroethylating agents (Dolan et al, Cancer Research, 46, pp. 4500-4504, (1986)). Subsequent studies demonstrated that there was a dose dependent decrease in AGT levels in human colon xenograft tumors carried in nude mice after intraperitoneal injections of O.sup.6 -methylguanine (Dolan et al, Cancer Chemother. Pharmacol., 25, pp. 103-108, (1989)). However, these compounds were not potent enough to be likely to be useful for treatment of patients since the rate of AGT depletion was slow and the extent of depletion was not complete even with very high doses.
O.sup.6 -benzylguanine differs from O.sup.6 -methyl- and O.sup.6 -n-butylguanine in that the alkyl substituent is replaced with a benzyl group and it is a known intermediate compound. See Bowles et al, J. Med. Chem., 6, pp. 471-480 (1963); Frihart et al, J. Am. Chem. Soc., 95, pp. 7174-7175 (1973). However, the use of this compound in chemotherapeutic treatment has yet to be reported.